Researchers Discover Cells that Restore Bladder’s Unique Lining

Led by Cathy Mendelsohn, PhD, an associate professor of urology, pathology and cell biology, and, genetics and development and a member of the Columbia Stem Cell Initiative, the study found that these progenitor cells need retinoic acid, a derivative of Vitamin A, to make the inner lining of the bladder and to regenerate the lining after damage. This raises the possibility that retinoids could be used to help prevent degradation of this important biological barrier in patients with chronic injury, which can lead to permanent bladder damage.

Identification of the progenitor cells responsible for regeneration may also help tissue engineers design ways to create new bladder tissue for cancer patients and others who have had their bladder removed. The findings were published Sept. 16 in Developmental Cell.

The bladder’s inner lining is like no other biological barrier in nature. The multi-layered lining—called the urothelium—prevents leakage under pressure, fends off pathogens with a unique protein barrier, and protects underlying neurons, muscle, and blood vessels from toxins in the urine.

Cells in the barrier rarely divide, but acute damage from urinary tract infection or exposure to toxins induces rapid regeneration: The upper layer of the urothelium sloughs off and progenitors in the intermediate layer produce cells that form a new upper layer.

Multiple rounds of injury can compromise regeneration of the outer layer, resulting in permanent scarring, bladder dysfunction, and chronic pain.

“In chronic conditions such as bladder pain syndrome (aka interstitial cystitis), a disease that affects primarily women, underlying tissue including nerve endings is exposed, and that is thought to be a cause of chronic pain,” Mendelsohn says. “In the most severe cases, the treatment for bladder pain syndrome and other chronic diseases is removal of the bladder.”

These clinical observations led to the idea that progenitor cells in the adult urothelium can be damaged or eliminated by continuous injury—and that protecting them may help patients with chronic conditions —but the identity of the progenitor cells was unclear.

Mendelsohn’s lab showed that there are two different urothelial progenitor populations, one that exists for a short time in the embryonic urothelium, and a second one in adults that regenerates the barrier’s outer layer after damage.

By using fluorescent tags to trace the progeny of cells in different layers, Mendelsohn’s team tested the longstanding idea that basal cells are the progenitors of the lining’s outer layer; they found, however, that the basal cells could create only new basal cells.

Instead, they traced formation of the outer urothelium in a developing embryo to a new cell type, P-cells, which disappear before birth. In adults, they showed that cells in the urothelium’s middle layer can self-renew and regenerate the urothelium’s outer layer. Both types of progenitor cells depend on retinoic acid for their functions.

Though the study was conducted in mice, Mendelsohn says it’s likely that human urothelium is created by the same progenitors. Her lab is now looking for such cells.